Adaptations to hypoxia have been considered in the sequence of oxygen transport from air to lung, lung to blood, and blood to tissues. We find that the drive to breathe during hypoxia is an inherited characteristic in normals, athletes and persons with lung disease, and it may correlate with the adequacy of breathing in lung disease. Investigation into ventilatory stimulants, progesterone and acetazolamide, has provided clues to mechanisms of ventilatory control and possible modes of therapy. In the pulmonary circulation, vasoactive substances such as histamine and the prostaglandins are largely modulators of tone and their activity may vary with post-natal age. The major constrictor of lung arteries, hypoxia, may be mediated through metabolic processes involving calcium possibly acting directly on the vascular smooth muscle. An increase in pulmonary arterial pressure recruits capillaries, speeds velocity of red cells in them and increases the surface area for lung oxygen transfer. Species with no collateral ventilation are particularly prone to vasoconstrictor effects of hypoxia. Abnormal pulmonary ventilation and pulmonary circulatory control appear to be involved in high altitude pulmonary edema, chronic mountain sickness, and pregnancy at high altitude in sleeping and awake subjects.